tbuckley/cabot-search huggingface dataset:
Combination polypectomy or excisional biopsy with interventional radiology local tumor destruction versus polypectomy or excisional biopsy for colon cancer: A SEER database analysis.
Authors: Ashton Legenza, Michael Burdyny, Peter T. Silberstein, Connor Tupper
Journal: Journal of Clinical Oncology (2023)

e15657 Background: Colon cancer is one of the most common forms of cancer, affecting millions of individuals worldwide. Despite advances in surgical and systemic therapies, a significant proportion of patients still present with locally advanced or metastatic disease. Interventional radiology has emerged as a crucial tool in the management of colon cancer, offering a number of minimally invasive treatments aimed at locally destroying the tumor. This study aims to assess the effectiveness and prognostic impact of various interventional radiology treatments for colon cancer. Methods: We queried the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed with primary colon cancer from the cecum to the sigmoid (primary site codes C180-189), including the appendix, diagnosed between 2000-2019. Patients were included if management of the primary tumor included either excisional biopsy, polypectomy, and/or local tumor destruction (LTD) via photodynamic therapy, electrocautery, cryosurgery, or laser ablation (surgical codes 21-24). Variables included for Kaplan-Meier, Chi-square, and Cox Regression analyses were age at diagnosis, sex, race, stage, and surgical management subtype status. Results: A total of 18164 patients were collected from this search of which 775 patients underwent a combination polypectomy or excisional biopsy with LTD, 6997 patients underwent polypectomy alone, 1619 patients underwent excisional biopsy alone, 7959 patients underwent endoscopic polypectomy alone, 814 patients underwent a surgical excision polypectomy alone. On Kaplan-Meier, the combination polypectomy or excisional biopsy with LTD showed better survival than excisional biopsy alone (p &lt; 0.001). The combination treatment showed similar survivability to polypectomy NOS, endoscopy polypectomy alone, and surgical excision polypectomy alone. The one-, three-, and five-year survival rates of combination treatment were 97.0%, 94.7%, and 93.4%, respectively, which is significantly greater than excisional biopsy at all time points (p’s &lt; 0.001) and within 1% of all other treatments at all time points. On Cox regression, no differences in survival were observed between groups. Of note the demographics of older age (p &lt; 0.001), black race (p &lt; 0.001), American Indian/Alaska Native (p = 0.044), regional spread of tumor ( &lt; 0.001), and distant spread of tumor (p &lt; 0.0001) were all associated with worse survival outcomes. Conclusions: Combination polypectomy or excisional biopsy with interventional radiology LTD procedures are associated with improved survival compared to excisional biopsy alone for the treatment of colon cancer. Our results suggest these interventional radiology procedures may be effective additional management options for the management of primary colon tumors.
Investigator-initiated phase 1 clinical trial of synthetic TIL: Autologous peripheral T cells engineered with polyclonal TIL-derived TCRs.
Authors: Zhongping Cheng, Wei Wu, Jiekun Xuan, Yue Zhao, Jun Cai, Ely Porter, Xi Chen
Journal: Journal of Clinical Oncology (2023)

e14525 Background: The efficacy of tumor-infiltrating lymphocyte (TIL) therapy is limited by the rarity of anti-tumor TCRs and exhausted status of the product. Its improvement should focus on a high frequency of diverse anti-tumor TCRs with stem-like phenotype, which can be achieved synthetically by identifying multiple anti-tumor TCRs from the patient's intra-tumor TCR repertoire and subsequently engineering them into the patient’s peripheral T cells. Such a ‘synthetic TIL’ is cost-prohibitive using existing technologies. To enable a synthetic TIL product, we developed ultra-high throughput TCR gene synthesis and screening methods to synthesize and screen &gt; 50,000 TCRs from scRNA-Seq data from &gt; 30 patients and identified &gt; 100 tumor/NeoAg-reactive TCRs. The gene expression patterns of the T cells carrying such experimentally validated tumor/NeoAg-reactive TCRs gave rise to an algorithm called Interpreter to predict potentially anti-tumor TCRs from scRNA-Seq data. Methods: To translate synthetic TIL to the clinic, we developed a method to generate up to 100 sequence-verified TCR-encoding plasmids (selected by Interpreter) from fresh tumor biopsy in just 3 weeks. Our GMP-grade production uses a collective knock-in approach, where a mixture of up to 100 plasmids (each encoding a distinct TCR) at equal proportion are packaged into AAV which serve as template to precisely insert the TCR genes into a primarily monoallelic locus and simultaneously inhibit the endogenous TCR. This gene editing is characterized by a modified scRNA-Seq method called EntrySeq. In first-in-human, N-of-1 trials, 10 9 to 6x10 9 synthetic TIL cells were administered to solid tumor patients with or without lymphodepletion and IL2. An investigator-initiated Phase 1 trial was then opened to evaluate safety, preliminary efficacy, and cellular activity of synthetic TIL and to determine RP2D and MTD. Subjects with relapsed, unresectable locally advanced solid tumors who received at least 1 standard systemic therapy are allowed to enroll in this study. Those patients with no standard treatment regimens available, or those who are unable to obtain effective treatment due to economic conditions are also permitted. Results: EntrySeq confirmed that &gt; 80% of the T cells express only 1 TCR, avoiding mispairing of different TCRs. The frequencies of different TCRs were largely uniform and were stable through plasmid, AAV and T-cell mixtures. Up to 1.5x10 10 synthetic TIL cells were produced from a patient’s leukopak. 40 to 60% of the T cells in the product for infusion express an exogenous TCR. In first-in-human trials, the administered T cells showed favorable persistence and safety profile. The Phase 1 trial is ongoing. Conclusions: We established a fast, affordable, and GMP-compliant process to manufacture synthetic TIL products, enabling a Phase 1 trial.
Post-marketing surveillance safety analysis of patients with CNS malignancies treated with tumor treating fields (TTFields) therapy between 2011–2022.
Authors: Maciej M. Mrugala, Wenyin Shi, Fabio Iwamoto, Rimas Vincas Lukas, Joshua David Palmer, John H. Suh, Martin Glas
Journal: Journal of Clinical Oncology (2023)

2049 Background: Glioblastoma (GBM) has a poor prognosis. Standard treatments are associated with systemic toxicity, further increasing the disease burden in this patient population. Tumor Treating Fields (TTFields) are electric fields that disrupt cancer cell processes which affect cancer cell viability, and are generated by a portable, wearable device which is locoregional and noninvasive. TTFields therapy was approved by the FDA for the treatment of newly diagnosed (nd) and recurrent (r) GBM based on the phase 3 EF-14 (TTFields therapy 200 kHz + temozolomide) and EF-11 (TTFields 200 kHz) studies, respectively. TTFields therapy is also approved for pleural mesothelioma. We report an updated global, post-marketing surveillance (PMS) safety analysis of patients with CNS malignancies treated with TTFields therapy over an 11-year timeframe. This analysis represents the largest dataset of TTFields therapy use to date. Methods: Unsolicited safety data were collected from routine post-marketing activities for patients (N = 25,898) in North America, Europe, Middle East and Africa and Japan, from October 2011 to March 2022. AEs were stratified by diagnosis, age, and sex and categorized using MedDRA version 25.1. Results: Diagnoses were ndGBM (68%), rGBM (26%), anaplastic astrocytoma/oligodendroglioma (4%) and other (2%). Baseline demographics were reflective of real-world practice: median (range) age was 59 (3–103) years; two-thirds of patients were male. Most (69%) patients were 18–65 years; 0.4% were &lt; 18 years, and 30% were &gt; 65 years. All-cause and TTFields-related AEs occurred in 18,798 (73%) and 14,599 (56%), patients, respectively. The most common device-related AE was skin reaction (43% patients overall). There were no major differences in occurrence of this AE between pediatric, adult, and elderly groups (39%, 42%, and 45%, respectively), or between males and females (41% and 46%, respectively). The incidence of device-related skin reactions was higher in ndGBM than rGBM (46% vs 34%, respectively), in line with previous reports. Only 405 (2%) of patients overall reported an AE of treatment-related ‘quality-of-life decreased’. In line with the phase 3 studies, there were no treatment-related systemic AEs. Conclusions: In this updated global PMS safety analysis, TTFields therapy demonstrated a tolerable safety profile in patients with CNS malignancies, with no new safety findings. In line with previous real-world and clinical data, most AEs were localized, non-serious skin events, which were consistent between age groups. Such events can typically be managed easily using prophylaxis and topical therapies, together with optimization of caregiver techniques. Importantly, no TTFields therapy-related systemic AEs were detected.
Maintenance therapy with a poly(ADP-ribose) polymerase inhibitor (PARP) in patients with newly diagnosed ovarian cancer: A systematic review and meta-analysis.
Authors: Carlos Stecca, Maysa Vilbert, Isabella Michelon, Caio Castro, Maria Inez Dacoregio, Fabio Fin, Audrey Tieko Tsunoda, Andreia Cristina De Melo, Alexandre Andre B. A. Da Costa
Journal: Journal of Clinical Oncology (2023)

e17587 Background: PARP inhibitors (PARPi) have been approved for maintenance therapy in newly diagnosed ovarian cancer patients with or without homologous recombination deficiency (HRD). In this meta-analysis, the latest clinical data to assess the efficacy and safety of this approach across different subgroups were synthesized. Methods: PubMed, Scopus, and Cochrane databases were searched for randomized controlled trials that compared maintenance PARPi with placebo in newly diagnosed ovarian cancer. The outcomes of interest included progression-free survival (PFS) according to HRD status, overall survival (OS), second PFS (PFS2), and time-to-first subsequent treatment (TFST). Heterogeneity was examined with I 2 statistics. A random-effects model was used for outcomes with high heterogeneity. Results: A total of 6 Randomized clinical trials with 3609 patients were included, of whom 2348 (65%) received maintenance PARPi. PFS was significantly longer for HRD-positive patients receiving PARPi [Hazard ratio (HR) 0.44, 95% Confidence interval (CI) 0.37 – 0.52 p&lt;0.001] and for HRD-negative patients [HR 0.71, 95% CI 0.54 – 0.92 p=0.009]. Maintenance PARPi was associated with improved OS in HRD-positive patients [HR 0.59, CI 0.47 -0.73, p&lt;0.001] but not in unselected patients. PFS2 in the HRD-positive population was reported in three trials, and it favored the use of PARPi [HR 0.57, CI 0.43 – 0.76, p&lt;0.001]. Adverse events ≥grade 3 were more common in patients on maintenance PARPi (p&lt;0.001). The occurrence of myelodysplastic syndrome was numerically but not significantly higher in the PARPi group. Conclusions: Maintenance with PARPi in patients with newly diagnosed ovarian cancer significantly prolongs PFS regardless of HRD status. Moreover, PARPi maintenance improves OS and PFS2 in patients with BRCA and/or HRD-positive tumors compared to placebo. [Table: see text]
Incidence of other multiple primary malignancies in patients with adrenocortical carcinoma.
Authors: Hiren Koshiya, Vivek Pandav, Osama M. Mosalem, Jyothik Varun Inampudi, Jaydeepbhai Patel, Yanyan Lou, Rami Manochakian, Sarika Rao, Yujie Zhao
Journal: Journal of Clinical Oncology (2023)

e16621 Background: Adrenocortical carcinoma (ACC) is an exceedingly rare aggressive endocrine malignancy with about 1 new case per million people diagnosed annually in the US. Higher incidence of ACC has been reported in patients (pts) with inherited syndromes such as Lynch syndrome and Li-Fraumeni syndrome. However, the incidence rate of developing multiple primary cancers in this population is unknown. The aim of this study is to investigate the frequency of additional malignancies in ACC patients. Methods: Using the Mayo Clinic Cancer Registry, we identified 63 pts who were treated for ACC from 2010- 2018 with updated follow up data until 01/31/2023. Electronic medical records were reviewed. Results: Among the patient cohort, 22 pts were male. 18/63 (29%) pts were found to have at least one additional malignancy, including basal cell carcinoma (3/18, 17%), melanoma (3/18, 17%), thyroid cancer (3/18, 17%), prostate cancer (3/18, 17%), squamous cell carcinoma of skin (2/18, 11%), renal cell carcinoma (2/18, 11%), breast cancer (2/18, 11%), leukemia (2/18, 11%), lung cancer (1/18, 6%), transitional cell malignant neoplasm of kidney (1/18, 6%), squamous cell carcinoma of tonsil (1/18, 6%), ovarian cancer (1/18, 6%), seminoma (1/18, 6%) and bladder cancer (1/18, 6%). 8/18 (45%) pts had more than one (2-3) non-ACC malignancies. The median age at diagnosis of ACC was 56 years (02-83). The median age at diagnosis of non-ACC malignancies was 54 years (25-72). Most of the patients (13/18) were diagnosed with non-ACC malignancy within 5 years of diagnosis of ACC. Most pts (13/18, 72%) were diagnosed with non-ACC malignancy first. Germline mutation information was not available except for 2 pts with known family history (FH) of Lynch syndrome and 2 pt with a known FH of Li-Fraumeni syndrome. FH was available in 38 pts, out of which 29 pts had FH of cancer identified in first-degree relatives. Among the 18 pts with additional malignancies, 12 pts had FH of cancer in first-degree relatives. All except 2 pts underwent curative treatment for their non-ACC malignancies, and 14 pts had no evidence of disease at death or the time of last follow-up. Conclusions: The rate of other multiple primary malignancies in pts with ACC is high, indicating possible genetic predisposition associated with this disease; Early genetic consultation and evaluation for known and novel germline mutations may need to be considered for these pts to improve long-term outcomes.
Neoadjuvant short-course radiotherapy followed by chemotherapy plus camrelizumab versus long-course chemoradiotherapy followed by chemotherapy for patients with locally advanced rectal cancer: A randomized, multicenter, open-label phase 3 trial (Union).
Authors: Zhenyu Lin, Peng Zhang, Zhiguo Hou, Kaixiong Tao, Tao Zhang
Journal: Journal of Clinical Oncology (2023)

TPS3638 Background: Short-course preoperative radiotherapy (SCPRT) and long-course chemoradiotherapy (LCCRT) are standard neoadjuvant treatments for locally advanced rectal cancer (LARC). Further, the RAPIDO trial found that SCPRT combined with consolidation chemotherapy produced better short- and long-term outcomes than SCPRT alone for patients with high-risk LARC. A phase 2, single-arm trial of neoadjuvant SCPRT followed by camrelizumab (an anti-PD-1 antibody) plus chemotherapy demonstrated promising short-term outcomes in patients with LARC. The Union trial is evaluating the efficacy and safety of neoadjuvant SCPRT followed by camrelizumab plus chemotherapy versus LCCRT followed by chemotherapy in patients with LARC. Methods: The Union trial is enrolling patients aged 18-75 with histologically confirmed clinical stage T3-4/N + adenocarcinoma of the rectum, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a tumor inferior margin less than 10 cm above the anal verge. Eligible patients are randomized in a 1:1 ratio to either arm A or arm B. Patients in arm A receive neoadjuvant treatment with SCPRT (a total of 25 Gy in 5 days) followed by camrelizumab (200 mg/m 2 intravenous drip on day 1, every 3 weeks for 2 cycles) plus CAPOX (oxaliplatin 130 mg/m 2 intravenous infusion over 2 hours on day 1, capecitabine 1000 mg/m 2 oral twice daily, days 1–14, every 3 weeks for 2 cycles), surgery, and adjuvant treatment with camrelizumab plus CAPOX (6 cycles) followed by camrelizumab until the medication duration of camrelizumab reaches one year. Patients in arm B receive neoadjuvant treatment with LCCRT (capecitabine 825 mg/m 2 twice daily, 5 days a week, combined with a total dose of 50.4 Gy in 28 days) followed by CAPOX (2 cycles), surgery, and adjuvant treatment with CAPOX (6 cycles). Randomization is stratified by clinical T stage (≤T3 vs T4) and clinical N stage (N0 vs N + ). The primary endpoint is pathologic complete response (pCR). The secondary endpoints are 3-year event-free survival rate, overall survival, R0 resection rate, completion rate of neoadjuvant treatment, 3-year disease-free survival rate, tumor regression grading, safety, and quality of life. pCR is evaluated per the AJCC 8th Edition TRG scoring system as assessed by the blinded independent central review. Adverse events are graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Quality of life is assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30. This study began enrollment in July 2021 with a planned enrollment of 230 patients. Clinical trial information: NCT04928807 .
Willingness of women at increased genetic and non-genetic risk of breast cancer to participate in intervention trials to prevent cancer.
Authors: Cecilia Mastrogiacomo, Patricia Thompson, Anne Moyer, Christina Preece, Alison Stopeck
Journal: Journal of Clinical Oncology (2023)

e24190 Background: The factors that influence willingness to participate (WTP) in breast cancer (BC) prevention trials are not well understood. WTP in BC prevention trials was examined in patients at increased risk of BC considering intervention and participant characteristics. Methods: Women self-identifying as being at increased risk for BC were recruited to a cross-sectional study of WTP in BC prevention trials. 78% (87 of 112) of participants completed ≥50% of a 29 item Likert Scale questionnaire about WTP in BC prevention trials that varied in intervention type and intensity, duration, time commitment, study procedures, and side effects of medications. Responses were dichotomized into “more willing” (“a lot” and “moderately”) versus “less willing” (“some,” “a little,” and “not at all”). A chi-square test was used to determine if responses differed between participants based on intervention and participant characteristics. Results: General WTP in BC ‘prevention’ studies was high at 79% “more willing”, including 67% and 72%, respectively, for unspecified physical activity and diet behavior change interventions. WTP differed significantly for diet-based behavior change interventions by type and duration; WTP was significantly lower for 12- versus 3-month interventions for both eliminating foods (28% versus 53% “more willing”, p = 0.0007) and for engaging in intermittent fasting (30% versus 45% “more willing”, p = 0.042). For physical activity, WTP decreased with duration of the intervention with 28% fewer WTP for one hour of low intensity exercise/day when compared to 30 minutes (p &lt; 0.0001). For medications, less than half of participants (46%) expressed being “more willing” to participate, and WTP decreased significantly when possible side effects were presented (81% “less willing”) with 95% “less willing” for medications with a rare risk of serious side effects. WTP was influenced by BC risk gene mutation status, with higher proportions among gene carriers compared to non-gene carriers (59% versus 21% “more willing,” p = 0.0013), including WTP in medication chemoprevention studies (38% versus 8% “more willing,” p = 0.002). Conclusions: WTP in BC prevention trials of behavior change is high among patients at elevated risk of BC but for all women was found to be significantly negatively influenced by greater time commitment and duration of intervention beyond a few months. WTP in studies of medication is lower compared to behavior change, and very low for medications with any side effects. Overall, WTP is greater in women with known genetic risk. This study suggests that WTP may be influenced by how patients perceive their level of risk. These results also suggest that despite interest in behavior change prevention, patients may not fully recognize the relationship between sustained behavior change and potential for prevention benefit.
Safety, pharmacokinetics and anti-tumor activity of RP12146, a PARP1/2 inhibitor, in patients with locally advanced or metastatic solid tumors.
Authors: Piotr Jan Wysocki, Maciej Tadeusz Lubaś, Mateusz Łobacz,, Ewa Kalinka-Warzocha, Piotr Tomczak, Michal Kwiatek, Iwona A. Lugowska, Martin Smakal, Dominik Chraniuk, Bohuslav Melichar, Beate Markiewicz-Bialek, Kasi V. Routhu, Prajak J. Barde, Ajit Nair
Journal: Journal of Clinical Oncology (2023)

3097 Background: RP12146 is an orally bioavailable, potent small-molecule inhibitor of poly (ADP-ribose) polymerase (PARP) 1 and PARP 2. Pre-clinically, RP1246 demonstrated anti-proliferative activity in both BRCA and non- BRCA mutant cancer cell lines of different tumor types as well as in xenograft models. The first-in-human of RP12146 as a single agent is underway to determine the safety, pharmacokinetics and anti-tumor activity. Methods: The phase I/Ib study was designed as two-part study. Phase I was a dose escalation, 3+3 design, MTD determination study and would enroll pts who have tumors which are known to harbour DNA repair deficiencies. Phase Ib is dose expansion at the MTD/ optimal dose and would enroll thirty-six pts (12 pts each of advanced/metastatic ovarian cancer (OC), breast cancer (BC), and castration-resistant Prostate cancer (mCRPC) having a confirmed deleterious HRR mutation. RP12146 was administered orally in a 28-days cycles until disease progression. Safety were the primary outcome and the investigator-assessed ORR, CBR and PFS assessed using RECIST v1.1, are the secondary outcomes. Predictive biomarker analysis included inhibition of PARP enzyme as measured by gH2AX levels in PMBCs. Results: As of 31-Jan-2023, 9 pts in the dose escalation at 3 dose levels (100 mg QD, 200mg BID and 400 mg BID) and 13 pts (with 5 CHEK2, 4 BRCA2, 2 ATM, 1 CDK12, and 1 RAD51C mutations) in dose expansion have been enrolled. No DLTs were reported in dose escalation. The dose of 400mg BID was considered for dose expansion. Out of 22 pts enrolled, 13 pts had PC, 3 pts had OC, and 2 pts had BC. Most of the related AEs reported were mild in severity except one event of Grade 3 anaemia which resolved, and patient continues to be on therapy. None of the pts developed related SAEs or discontinued due to an AE. Eleven patients (50%) in the expansion group continue to be on RP12146 treatment. RP12146 exhibited rapid absorption achieving maximum concentrations in 1 hr, with an elimination half-life of ~ 4 hrs. Out of the 7 efficacy evaluable PC patients, 5pts showed stable disease and 2pts showed progressive disease. Out of 3 OC pts, 2 pts showed stable disease, and one pt had progressive disease. Among two BC pts, one showed stable disease and the other had progressive disease. Overall, out of 16 efficacy evaluable patients, 8 patients (50%) showed stable disease. Conclusions: RP12146 showed a differentiated safety profile so far with limited hematological toxicities reported as compared to the first-generation PARP inhibitors. Updated safety and efficacy data will be provided at the time of presentation. Clinical trial information: NCT05002868 .